The present invention relates to compositions suitable for treatment of inflammatory disorders and to methods utilizing same in treatment of inflammatory disorders such as cutaneous inflammatory diseases.
Inflammation occurs when tissues are injured by viruses, bacteria, trauma, chemicals, heat, cold or any other harmful stimulus. Chemicals including bradykinin, histamine, serotonin and others are released, attracting tissue macrophages and white blood cells to localize in an area to engulf and destroy foreign substances. During this process, chemical mediators such as TNFα are released, giving rise to inflammation. Inflammatory disorders are those in which the inflammation is sustained or chronic. One example of an inflammatory disorder is osteoarthritis.
Local inflammatory diseases include, for example, asthma, oral mucosal, gastrointestinal inflammation, ocular, nasal and aural inflammation and other steroid responsive inflammatory disorders and conditions. Cutaneous inflammatory diseases include for example, psoriasis, atopic dermatitis, scleroderma and other steroid responsive cutaneous inflammatory disorders conditions such as uremic pruritus and skin conditions associated with exposure to radiation and chemotherapy as well as exposure to environmental radiation and irritants.
Topical steroids have been used in the treatment of inflammatory disorders, as described in U.S. Pat. No. 3,934,013 to Poulsen and references cited therein. Typically, moderate to severe cases of psoriasis require use of a mid-potency steroid such as mometasone furoate (Elocon™) or even a high-potency steroid such as halobetasol (Ultravate™). Topical application of glucocorticoids may suppress the body's own production of cortisol by the adrenal glands, however, especially in the case of relatively high potent products. Accordingly, compositions for treating inflammatory disorders without utilizing mid-potency or high-potency steroids or with use of substantially reduced steroid concentrations would be very useful.
Palmitoylethanolamine (PEA), a member of the class of compounds known as N-acylethanolamines (NAEs), was discovered in 1957 by Kuehl et al (The Identification of N-(2-hydrooxytheyl)-palmitamide as a naturally occurring anti-inflammatory agent, J Am Chem Soc 1957, 79:5577).
PEA, or N-(2-hydroxyethyl)hexadecanamide (also known as palmitoylethanolamide or palmidrol), is a naturally occurring C16:0 fatty acid derivative wherein the carboxylate function is amidated by the primary amine of ethanolamine. N-acylethanolamine compounds are known to have anti-inflammatory and anti-nociceptive effects, as described in Lambert et al (Lambert D M, Vandevoorde S, Jonsson K O, Fowler C J. Curr Med Chem. 2002; 9:663-74); Lambert D M et al (Lambert D M, DiPaolo F G, Sonveaux P, Kanyonyo M, Govaerts S J, Hermans E, Bueb J, Delzenne N M, Tschirhart E J. Biochim Biophys Acta. 1999; 1440:266-74); Brown A J (Br J Pharmacol. 2007; 152(5):567-75); and U.S. Pat. No. 5,506,224 and United States patent application 2005/0054730. None of the above references discloses or suggests use of such compounds in combination with corticosteroids and the use thereof in treating inflammatory diseases or disorders.
Tri-cyclic antidepressants, described inter alia in U.S. Pat. Nos. 2,554,736, 3,438,981, 3,420,851, 3,534,041, 3,505,321, 4,013,639, 4,105,785, 6,368,814, have been used for years as anti-depression agents. Topical 5% doxepin hydrochloride (Zonalon™) cream is also used for treatment of moderate pruritus in adult patients with atopic dermatitis or lichen simplex chronicus. U.S. Pat. No. 7,335,371, assigned to CombinatoRx, discloses compositions formulated for topical administration, comprising as the sole active ingredients a tricyclic antidepressant and a corticosteroid, and their use in treating inflammatory disorders. This patent neither discloses nor suggests in any way the ability of compositions of the present invention to utilize a low-potency steroid in therapeutic situations wherein a mid-potency or high-potency steroid would otherwise be required; or to utilize a mid-potency steroid wherein a high-potency steroid would otherwise be required.
Sulfonamide-class carbonic anhydrase inhibitors such as sulfamate-substituted monosaccharides, of which topiramate is an example, have been long used as anti-convulsive compounds. Topical formulations containing such compounds are proposed for use in treatment of glaucoma and in the assessment of corneal function, as described in U.S. Pat. Nos. 5,059,613 and 5,242,937, and for eczema, as described in WO2007/067036. None of the above references discloses or suggests use of such compounds in combination with corticosteroids and their use in treating cutaneous inflammatory diseases and disorders.
Monoamine oxidase inhibitors (MAOI) and used as anti-depressive treatments and are described inter alia in U.S. Pat. Nos. 5,508,311, 5,792,799, 6,472,423, and 6,569,470. None of the above references discloses or suggests use of such compounds in combination with corticosteroids and their use in treating cutaneous inflammatory diseases or disorders.
Cannabinoids are described inter alia in U.S. Pat. Nos. 5,747,524, 5,596,106, 6,017,919, 6,432,984, 6,509,367, 6,645,985, and 7,169,942. Use of such compounds for treating psoriasis has been suggested (Namazi M R. J Eur Acad Dermatol Venereol. 2005 May; 19(3):319-22). None of the above references discloses or suggests use of such compounds in combination with corticosteroids and the use thereof in treating cutaneous inflammatory diseases or disorders.
While reducing the present invention to practice, the present inventors have uncovered that combined use of corticosteroids and PEA, as well as other compounds produces unexpected results in treatment of inflammatory disorders and that PEA has the potential to augment the therapeutic properties of steroids—including increasing therapeutic activity as well as reducing steroid associated adverse effects.